Comparison of Hydroxypropylcellulose and Hot-Melt ...

When extruding blends of metformin HCl and HPC GXF with screw configuration SC#1, a higher extruder torque was observed, ranging from 8&#;12%. Higher extrusion temperatures of 160 and 140 °C showed a higher operating torque than the lower temperatures 120 and 100 °C. In the case of HPMC HME 4M, a torque of 4&#;6% was only observed when extruding at 160 °C with screw configuration SC#1. Extrusion at 100, 120 and 140 °C showed minimum extruder torque (&#;3%) during the process. When the screw configuration was changed to a lower shear screw configuration SC#2, the torque remained around 8&#;12% in the case of HPC GXF, whereas melt granulation with HPMC HME 4M showed a minimum extruder torque at all temperatures. Extruder torque is an indication of the force the motor exerts to move the screws to push the material forward. A higher extruder torque in melt granulation sometimes indicates a better agglomeration or compaction of material into dense granules.

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Two different screw configurations were used for this study, as shown in Figure 1 . Screw configuration#2 provided moderate shear to the powder, with mixing elements rotating at 60°. Screw configuration#1, with mixing elements rotating at 90°, provided higher shear to the material. Blends were melt granulated at four processing temperatures of 160, 140, 120 and 100 °C using a powder feed rate of 20 g/min and screw speed of 100 rpm. The extrusion temperature and screw configuration were changed and the effect of these two process variables on granule properties was studied. Different temperature profiles used for this study are shown in Table 2

Care was taken to avoid the possibility that the exposure to high shear provided by screw configuration and feed rate could lead to a complete or partial melting of a drug at relatively high temperature. In this case, because the melted drug may also contribute to granulation, any melting of a drug will make it difficult to distinguish between the effects of the melted drug and polymer. To avoid such a situation, only API (metformin hydrochloride) was first passed through the barrel using specific temperature profiles, feed rates, screw configurations, and screw speeds planned for subsequent twin-screw melt granulation experiments. Screw shafts were then pulled out of the barrel. Both screw shafts, as well as the extruder barrel, were examined for any charring or the presence of molten, viscous material which could indicate the possible melting of the drug. If charring or the presence of molten material was observed, those process conditions were eliminated from any future experiments. Usually, the extrusion temperature is kept 30&#;40 °C below the melting point of the drug. Our initial temperature profile, based on preliminary experiments with HPMC HME 4M and metformin HCl, showed that the drug partially melted at the temperature of 180 °C. Therefore, the extrusion temperature of 180 °C was removed from the experimental design and a maximum extrusion temperature of 160 °C was used for all experiments. A feed rate of 20 g/min and screw speed of 100 rpm was kept constant for all experiments.

Different process variables can impact the final product characteristics in a melt granulation process. These process variables include screw speed, powder feed rate, screw configuration, and temperature profile. The granule properties may be impacted by high or low shear in the extruder barrel. The shear in the extruder barrel (at a specific extrusion temperature) can be varied by changing the screw speed and/or powder feed rate. An increase in feed rate and screw speed may increase the mechanical shear inside the extruder barrel to improve binding and agglomeration, and thus increase the granulation tendency of the polymer.

Using the minimum quantity of rate-controlling polymers in formulations, where the controlled release of a highly soluble, high-dose active is desired, is a major challenge for formulators. Twin-screw melt granulation can enable a formulator to use minimal amounts of these polymers to obtain controlled- or extended-release formulations of highly soluble actives. The concentration of a polymer in a melt granulation may vary from 10&#;30%depending on the desired drug release pattern. Some authors showed that the successful melt granulation of metformin HCl can be carried out even with a low concentration of polymers (<10%) [ 27 ]. These reports, however, targeted the immediate release of metformin HCl. From our experience, a polymer concentration minimum of 15&#;25%is required to obtain a controlled drug release with high-molecular-weight HPC and HPMC. Therefore, blends of 75%metformin HCl and 25%polymer were prepared for melt granulation.

In the case of HPMC HME 4M, when the processing temperature was varied from 100 °C to 160 °C, HPMC HME 4M granule quality showed a significant variability, as shown in Figure 2 b. For HPMC HME 4M, granules were only obtained at 160 °C. At lower temperatures, the polymer did not fully melt, yielding a fine powder and granules of an irregular nature. Nonetheless, it was anticipated that granules obtained with HPMC HME 4M may still provide adequate tablet strength. When the screw configuration was changed to a lower shear, SC#2, fine particles were obtained at all temperatures. There was no change in the appearance of the melt-granulated particles in the feed blend. This showed that HPMC HME 4M required a higher shear in the extruder to melt, and a low shear screw configuration was inadequate for providing shear to the polymer for melting and granulation.

In twin-screw melt granulation, process conditions, as well as the melt viscosity of the binder, can impact the granule properties. Using screw configuration SC#1 for the extrusion of HPC GXF, granule shape and appearance were affected when the processing temperature was varied from 100 to 160 °C, as shown in Figure 2 a. At a lower processing temperature of 100 °C, the granules were hard agglomerates (centimeter), but smaller in size. As the temperature was increased from 100 to 120 °C, the granule morphology changed to more ribbon-like granules. At higher temperatures of 140 and 160 °C, the granules produced were more consistently continuous and ribbon-shaped. The granule morphology indicated that, at higher temperatures, HPC had a lower melt viscosity and increased binding capacity to bind and agglomerate metformin HCl to produce ribbon-shaped granules. It was apparent that these granules or extrudates were to be milled to produce smaller particles that could provide an acceptable flow for tableting. When the screw configuration was changed to a low shear SC#1, no significant change in granule morphology was observed. Ribbon-like extrudates were obtained at high temperatures of 140 and 160 °C and hard agglomerates were obtained at 100 and 120 °C.

In the case of HPMC HME 4M, milled granules obtained at 100, 120 and 140 °C with screw configuration SC#1 simply passed through the screen during milling. When this powder was analyzed using sieve analysis, most of the particles (>98%) in these samples were <125 µm. Granules obtained at 160 °C also passed through the screen without any potential milling. When these granules were analyzed using sieve analysis for particle size distribution, these powders had a lower number of fines (<125 µm). The particle size distribution of milled granules obtained at 140 and 160 °C with HPC GXF and HPMC HME 4M is shown in Table 3 . When melt-granulated samples of metformin HCl and HPMC HME 4M, obtained using a low shear screw configuration, were milled, all samples simply passed through the screen. When these milled granules were analyzed by sieve analysis, in all cases more than 98% of particles were less than 125 µm. Therefore, only when using a high shear screw configuration SC#1 and high temperature of 160 °C, could a lesser proportion of fines (<125 µm) be obtained in the case of HPMC HME 4M. The powder yield after milling in all cases was close to 100%, as there were no hard agglomerates present in this case, and thus no retention on the screen.

Granules obtained from melt granulation of metformin HCl with HPC GXF and HPMC HME 4M were milled using a co-mill. After milling samples were collected using screw configuration SC#1 in melt granulation, the ribbon-shaped extrudates were reduced to a powder. Particles obtained after milling of 100 and 120 °C granules showed a higher number of particles, less than <125 µm compared to 140 and 160 °C. This was due to the higher binding capacity of HPC GXF at a higher temperature. When melt-granulated samples, obtained with lower shear screw configuration SC#2, were milled, the particle size distribution remained comparable to that obtained with SC#1. Because these agglomerates are extremely hard and dense, some of these hard agglomerates remained in the mill and did not pass through the screen. The overall yield after milling was 85&#;90%.

Tablets were compacted using the milled granules at compaction forces of 15 and 30 kN. In the case of HPC GXF, tablets with acceptable hardness were obtained in all cases irrespective of the screw configuration or processing temperature. This showed that HPC GXF has a high binding capacity, even at low temperatures of 100 and 120 °C and with a minimum shear contributed from the screw configuration SC#2. HPMC HME 4M tablets obtained with extruded granules at 100, 120 and 140 °C were capped on compression. Only the HPMC HME 4M extrudate processed at 160 °C, with the high shear screw configuration SC#1 yielding coherent, strong tablets suitable for dissolution testing. No tablets were obtained with extrudates processed at any temperature with the low shear screw configuration SC#2. This indicated that HPMC HME 4M required a higher shear and temperature to fully melt and provide binding capacity. In contrast, HPC GXF-containing formulations were readily extrudable, yielding a consistent, molten extrudate over the entire processing temperature range of 100 to 160 °C. All the formulations that yielded tablets are shown in Table 4

3.6. Dissolution and SEM

Both HPMC HME 4M and HPC GXF have a similar molecular weight and viscosity; they are used for controlled-release tablet formulations. Tablets obtained from melt-granulated samples of metformin HCl with HPMC HME 4M and HPC GXF compressed at a compaction force of 15 kN were selected for dissolution studies.

w

/

w

for HPC GXF at one hour) as shown in

These tablets yielded similar dissolution profiles, regardless of the process temperature when compared at similar compaction forces. HPC GXF tablets compressed at 30 kN showed a further decrease in dissolution profiles which could be attributed to a decreased porosity. Dissolution profiles for tablets with melt-granulated samples of metformin HCl and HPMC HME 4M or HPC GXF were similar in the late time phase but HPMC HME 4M-based formulations had a higher burst effect compared to HPC GXF (69% in the case of HPMC HME 4M as compared to 44%for HPC GXF at one hour) as shown in Figure 3

Since the molecular weights of HPC GXF and HPMC HME 4M are comparable, both the polymers should provide similar swelling and drug release profiles. To investigate the burst release of the drug seen in the case of HPMC HME 4M, the SEM of the edge of the tablet was performed after one hour of the dissolution study. SEM micrographs showed the presence of large pores in the tablet in the case of HPMC HME 4M (shown in Figure 4 ), which explained the faster release of the drug through the matrix compared to HPC GXF. Tablets with HPC GXF showed very small pores in the matrix.

Rotational melt rheology: To provide efficient binding and granule properties, a polymer is required to regulate melt viscosity, so that it can deform and bind the particles together to provide granules. The rheological analysis of the polymer can guide a formulator on minimum processing temperature required for melt granulation process. The granulation capacity of the polymer may depend on its melt viscosity; therefore, a minimum processing temperature is required for a polymer to have an adequate low viscosity (or plasticity), so that it can deform itself and glue the drug particles to form the granules. In general practice, a parallel plate rheological study provides a basic idea on the selection of the minimum extrusion temperature required for the polymer. Glass transition temperature measured by differential scanning calorimeter (DSC) is not a sufficient indicator for guiding a formulator to choose the minimum extrusion temperature. The minimum extrusion temperature required by the polymer is often many degrees higher than its glass transition temperature measured by DSC.

6 Pa &#;s, to a glass-rubbery transition state, which is in between 104 and 105 Pa·s, eventually reaching its plastic state, which is below 104 Pa·s. In contrast, the continuous decrease in the complex viscosity from 106 to 104 Pa·s is monitored for HPC GXF because of its relatively lower glass transition temperature. Although it was reported that the complex viscosity should optimally be in the range of 103 to 104 Pa·s to enable melt extrusion, relying only on the complex viscosity is inadequate for selecting the right operational temperature for melt granulation, because it is not required that the polymer is fluid enough or has a low enough viscosity to dissolve the drug when flowing through the barrel and die in the extruder during melt granulation [

Because the extrusion process is more relevant to the polymer&#;s rheological properties, the minimum extrusion temperature could be indicated by the damping factor and tan δ value from a rheological temperature sweep. The minimum extrusion temperature is often higher than the polymer&#;s glass transition temperature, beyond which the tan δ starts increasing as a function of the temperature, indicating that the polymer chains overcome the intra- and inter-chain entanglements and start the plastic deformations. A temperature ramp from 90 °C to 200 °C is applied to investigate the effect of the temperature on the rheological behaviors of HPMC and HPC. The glass transition temperatures of HPMC HME 4M and HPC GXF are reported at 115 °C [ 31 ] and 84 °C [ 32 ], respectively; therefore, the temperature ramp tested is directly in the range of interest. The complex viscosity and tan δ as a function of the temperature are depicted in Figure 5 . As expected, both HPMC HME 4M and HPC GXF show decreases in the complex viscosity with the increase in the temperature. Specifically, the two stages&#; decrease in complex viscosity is observed for HPMC HME 4M because the low temperature end is below its glass transition temperature. The complex viscosity decreases from its glass state, which is above 10Pas, to a glass-rubbery transition state, which is in between 10and 10Pa·s, eventually reaching its plastic state, which is below 10Pa·s. In contrast, the continuous decrease in the complex viscosity from 10to 10Pa·s is monitored for HPC GXF because of its relatively lower glass transition temperature. Although it was reported that the complex viscosity should optimally be in the range of 10to 10Pa·s to enable melt extrusion, relying only on the complex viscosity is inadequate for selecting the right operational temperature for melt granulation, because it is not required that the polymer is fluid enough or has a low enough viscosity to dissolve the drug when flowing through the barrel and die in the extruder during melt granulation [ 17 ]. Moreover, the relatively close absolute values of the complex viscosity of both polymers make it very difficult to distinguish which is a better binder for the melt granulation process. However, tan δ seems to be a more reliable indicator for guiding the melt granulation temperature selection rather than the complex viscosity. In Figure 5 , tan δ signals successfully capture the glass transition of HPMC HME 4M, reflected by the peak around 119 °C. It is reported that the lower glass transition temperature is sufficient to significantly widen the processing temperature window of this HPMC HME 4M, but the tan δ also indicates that the minimum temperature needed to enable its plastic-dominant deformation is about 159 °C. On the contrary, the tan δ of HPC increases from 90 °C and reaches a semi plateau at 139 °C, indicating the melt granulation of HPC is possible when the temperature is above 90 °C. In summary, HPC should be a better melt granulation binder than HPMC HME 4M, with a broader processing temperature window, while HPMC HME 4M is only processable above 159 °C. The conclusion based on the rheological analysis is consistent with what was observed in melt granulation process.

η = η &#; + ( η 0 &#; η &#; ) × [ 1 + ( λ γ &#; ) α ] ( n &#; 1 ) α

(1)

η

0 and

η

&#; are the zero shear and infinite shear viscosity,

λ

is the relaxation time,

n

is power law index and

α

describes the transition region width. It was also reported that the infinite shear viscosity is very difficult to observe experimentally because the shear rate required for detecting it is very high and outside the normal measurement range. In this study, we could not capture the infinite shear viscosity for both samples. To obtain a more accurate curve fitting,

η

&#; was set to zero.

Aside from the processing temperature, the shearing force provided by the extruder contributes to the extrusion and deformation of the polymer. Therefore, a better understanding of the relationship between the shearing force and polymeric deformation is the key to guide robust screw design and the melt granulation process. Considerable efforts were devoted to establishing the structure&#;processing relationship via a rheological frequency sweep. Measurements of the complex viscosity at various frequencies at a single temperature can show if increasing the shear rate inside the extruder, either by increasing the screw speed or changing the screw configuration, is likely to improve the melt granulation. In this study, frequency sweeps within the linear viscoelastic region are conducted at low strains (<0.05) across an applied frequency range of 0.1 to 600 rad/s at different temperatures. Subsequently, the frequency sweeps are shifted into one master curve at the reference temperature of 140 °C by means of time-temperature superposition (TTS). Finally, the resulting complex viscosity profile from the master curve was fitted to the Carreau-Yasuda equation, which has a mathematic equation:whereandare the zero shear and infinite shear viscosity,is the relaxation time,is power law index anddescribes the transition region width. It was also reported that the infinite shear viscosity is very difficult to observe experimentally because the shear rate required for detecting it is very high and outside the normal measurement range. In this study, we could not capture the infinite shear viscosity for both samples. To obtain a more accurate curve fitting,was set to zero.

Figure 6 displays the complex viscosity&#;frequency data of HPMC HME 4M and HPC GXF in one master curve at the reference temperature of 140 °C. As shown in the figure, the TTS enables us to cover the rheological property of interest at 140 °C over a relatively broad frequency (time) range (~16 orders), which typically is not feasible when utilizing a single-frequency sweep because of the extremely long experimentation times and increased risk of sample degradation. Complex viscosity is one of the most important rheological properties that describes the processability of a material and can be directly correlated with molecular structure. In this study, both polymers show a typical shear-thinning behavior of polymeric melt, thus their complex viscosities display a strong dependence on the shear rate. Interestingly, both polymers show similar zero-shear viscosity due to their comparable molecular weights. Dependent on the substitution chemistry differences, however, the complex viscosity of HPC displays a stronger sensitivity to shear rate than HPMC does, manifested by a more pronounced shear thinning performance. In addition, other rheological properties, including relaxation time, the width of the transition region and power law index, have also changed correspondingly.

As a result, the master curves exhibited in Figure 6 are in good agreement with the modified Carreau-Yasuda model and the parameters fitting is conducted with sufficient accuracy. All obtained model parameters are summarized in Table 5 . In this manner, the rheological properties of HPMC HME 4M and HPC GXF, including the first Newtonian plateau, transition region, and shear thinning region, can be described, and compared quantitatively. Based on the fitting relaxation time, HPC shows one order less relaxation time than HPMC, indicating that it is more plastic and more easily deformed than HPMC under this temperature, making it a better melt granulation binder.

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We retain bettering and perfecting our goods and service. At the same time, we perform actively to do research and enhancement for China HPMC, Hydroxypropyl Methyl Cellulose, Welcome to visit our company, factory and our showroom where displays various products that will meet your expectation. Meanwhile, it is convenient to visit our website, and our sales staff will try their best to provide you the best service. Please contact us if you need more information. Our aim is to help customers realize their goals. We are making great efforts to achieve this win-win situation.
CAS:-65-3

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Hydroxypropyl MethylCellulose (HPMC) are widely used in construction, pharmaceutical,food, cosmetic, detergent, paints, as thickener, emulsifier, film-former, binder, dispersing agent, protective colloids.We can provide the regular grade HPMC, we also can provide modified HPMC according to customer requirements. After modified and surface treatment, we can get the goods which is dispersed in water quickly, lengthen open time, anti-sagging, etc.

Appearance White or off-white powder Methoxy ( % ) 19.0~ 24.0 Hydroxypropoxy ( % ) 4.0 ~ 12.0 pH 5.0~ 7.5 Moisture ( % ) &#; 5.0 Residue on ignition ( % ) &#; 5.0 Gelling temperature ( &#; ) 70~ 90 Particle size min.99% pass through 100 mesh Typical grade Viscosity(NDJ, mPa.s, 2%) Viscosity(Brookfield, mPa.s, 2%) HPMC MP400 320-480 320-480 HPMC MP60M - - HPMC MP100M - - HPMC MP150M - - HPMC MP200M - Min HPMC MP60MS - - HPMC MP100MS - - HPMC MP150MS - - HPMC MP200MS - Min

Typical Applications of HPMC:

Tile Adhesive

&#;Good water retention: prolonged opening time will make tiling more efficient.

&#;Improved adhesion and sliding resistance: especially for heavy tiles.

&#;Better workability: lubricity and plasticity of plaster is ensured, mortar can be applied easier and quicker.

Cement Plaster / Dry mix mortar

&#;Easy dry mix formula due to cold water solubility: lump formation can be easily avoided, ideal for heavy tiles.
&#;Good water retention: prevention of fluid loss to the substrates, the appropriate water content is kept in mixture which guarantees longer concreting time.
&#;Increased water demand: increased open time, expanded spry area and more economical formulation.
&#;Easier spreading and improved sagging resistance due to improved consistency.

Wall putty

&#;Water retention: maximized water content in slurry.
&#;Anti-sagging: when spreading a thicker coat corrugation can be avoided.
&#;Increased mortar yield: depending on the weight of the dry mixture and appropriate formulation ,HPMC can increase the mortar volume.

Exterior Insulation and Finish System ( EIFS )

&#;Improved adhesion.
&#;Good wetting ability for EPS board and substrate.
&#;Reduced air entrancement and water uptake.

Self-leveling

&#;Protection from water exudation and material sedimentation.

&#;No effect on slurry fluidity with low viscosity

HPMC, while its water retention characteristics improve the finish performance on the surface.

Crack Filler

&#;Better workability: proper thickness and plasticity.
&#;Water retention ensures prolonged work time.
&#;Sag resistance: improved mortar bonding ability.

Pharmaceutical excipient and food application&#;

Usage Product grade Dosage Bulk Laxative 75K,75K 3-30% Creams, Gels 60E,65F,75F 1-5% Ophthalmic Preparation 60E 01.-0.5% Eye drops preparations 60E, 65F, 75K 0.1-0.5% Suspending agent 60E, 75K 1-2% Antacids 60E, 75K 1-2% Tablets binder 60E5, 60E15 0.5-5% Convention Wet Granulation 60E5, 60E15 2-6% Tablet coatings 60E5, 60E15 0.5-5% Controlled Release Matrix 75K,75K 20-55%

Packaging:

HPMC Product is packed in three layer paper bag with inner polyethylene bag reinforced , net weight is 25kg per bag.

Storage:

Keep it in cool dry warehouse,away from moisture, sun,fire,rain.

If you are looking for more details, kindly visit Hydroxypropyl Methyl Cellulose (HPMC) Powder.